Nitration and inactivation of manganese superoxide dismutase in chronic rejection of human renal allografts.

MacMillan-Crow, L.A.; Crow, John P.; Kerby, Jeffrey D.; Beckman, Joseph S.; Thompson, John A.

doi:10.1073/pnas.93.21.11853

Cited by 738 publications

(509 citation statements)

References 66 publications

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“…PN nitrates an essential tyrosine residue in Mn-SOD with the participation of manganese catalysis. In fact, our results suggest that the nitration of tyrosine within Mn-SOD might be a mechanism leading to a significant reduction of its activity (Mac-Millan-Crow et al, 1998), and a -Crow et al, 1996). This study is the first to suggest that the degree of nitration of this enzyme may also be a molecular footprint of vascular aging.…”

Section: -12mentioning

confidence: 51%

“…Nitration of tyrosine is the underlying mechanism of prostacyclin synthase inhibition by PN (Zou et al, 1997). Evidence for the in vivo formation of PN has been derived from immunohistochemical detection of NT in human atherosclerotic lesions and in the tissue of rejected human renal allografts (MacMillan-Crow et al, 1996). Recent indirect evidence (Leeuwenburg et al, 1998) suggests that specific enzymes may selectively accumulate oxidative damage during aging.…”

Section: Introductionmentioning

confidence: 99%

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Superoxide as a Messenger of Endothelial Function

Ullrich

Bachschmid²

2000

Biochemical and Biophysical Research Communications

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Section: -12mentioning

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Superoxide as a Messenger of Endothelial Function

Ullrich

Bachschmid²

2000

Biochemical and Biophysical Research Communications

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“…13,26,53 Here, evidence for reactive oxygen and nitrogen species involvement in airway epithelial cell apoptosis in asthma include the finding of increased nitrotyrosine in epithelial cells after inhibition of SOD in vitro, and in airway epithelial cells in vivo in asthma in other studies. 13,22,54 Other reports have shown that MnSOD is a target for tyrosine nitration and oxidation, 30,55 which leads to loss of enzyme function, subsequent oxidative damage of mitochondrial proteins, and ultimately cell death. 30,56 Here, we provide quantitative data on MnSOD oxidation and nitration in human asthmatic lungs.…”

Section: Discussionmentioning

confidence: 99%

Superoxide Dismutase Inactivation in Pathophysiology of Asthmatic Airway Remodeling and Reactivity

Comhair

Ghosh

et al. 2005

The American Journal of Pathology

170

144

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Airway hyperresponsiveness and remodeling are defining features of asthma. We hypothesized that impaired superoxide dismutase (SOD) antioxidant defense is a primary event in the pathophysiology of hyperresponsiveness and remodeling that induces apoptosis and shedding of airway epithelial cells. Mechanisms leading to apoptosis were studied in vivo and in vitro. Asthmatic lungs had increased apoptotic epithelial cells compared to controls as determined by terminal dUTP nick-end labeling-positive cells. Apoptosis was confirmed by the finding that caspase-9 and -3 and poly (ADP-ribose) polymerase were cleaved. On the basis that SOD inactivation triggers cell death and low SOD levels occur in asthma, we tested whether SOD inactivation plays a role in airway epithelial cell death. SOD inhibition increased cell death and cleavage/activation of caspases in bronchial epithelial cells in vitro. Asthma is commonly diagnosed using physiological measures, but alterations in airway structure are the defining features of asthma. Damage to airway epithelium, eosinophil infiltration, smooth muscle hyperplasia, thickening and aberrant collagen, and protein composition of the basement membrane are well established elements of the asthmatic airway. 1,2 The injury to the bronchial epithelium in asthma is marked by loss of columnar epithelial cells. Extensive loss of cells and denuded basement membrane with few basal cells remaining on the airway surface are noted in severe asthma, but shedding of airway epithelium is present even in clinically mild asthma. 2,3 Physical loss of epithelial lining cells is considered one proximate cause of the airway hyperresponsiveness to inhaled mediators, and has been speculated to contribute to asthmatic airway remodeling, in particular abnormal collagen synthesis. Evidence from organ culture systems supports the concept of an epithelial-mesenchymal unit in which loss of epithelium leads to mucosal myofibroblast and fibroblast proliferation, and collagen deposition. 2,4 -6 Thus, if the epithelial injury and loss could be understood and prevented in asthma, the clinical symptoms of airway hyperresponsiveness and long-term progressive sequelae in the airways, which contribute to fixed airflow limitation, might be prevented.Several reports have proposed that loss of epithelial cells is because of apoptosis based on immunostaining for the proteins that regulate apoptosis, or by detection of DNA strand breaks by immunostaining with the terminal dUTP nick-end labeling (TUNEL) assay. 7-11 However, not all reports have confirmed increased TUNEL positivity in airways. 9 Furthermore, if airway epithelial cells are undergoing increased cell death, it is unclear whether this is because of an inherent cell defect or a response to the asthmatic airway environment. Although nonspecific events related to increased levels of reactive oxygen and

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“…Tyrosine nitration is involved in many postischemic modifications [55][56][57]. Examples of proteins susceptible to inactivation by tyrosine nitration include mitochondrial superoxide dismutase [58,59] and several enzymes involved in oxidative energy metabolism, including aconitase [60], glutamate dehydrogenase [46], α-ketoglutarate dehydrogenase [61], and PDHC [46]. Because PDHC and α-ketoglutarate dehydrogenase complex share similar reaction mechanisms and an identical polypeptide subunit (E3), it is not surprising that they are both sensitive to enzyme inhibition by tyrosine nitration.…”

Section: Discussionmentioning

confidence: 99%

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

Richards

Rosenthal

Kristián

et al. 2006

Free Radical Biology and Medicine

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The pyruvate dehydrogenase complex (PDHC) is a mitochondrial matrix enzyme that catalyzes the oxidative decarboxylation of pyruvate and represents the sole bridge between anaerobic and aerobic cerebral energy metabolism. Previous studies demonstrating loss of PDHC enzyme activity and immunoreactivity during reperfusion after cerebral ischemia suggest that oxidative modifications are involved. This study tested the hypothesis that hyperoxic reperfusion exacerbates loss of PDHC enzyme activity, possibly due to tyrosine nitration or S-nitrosation. We used a clinically relevant canine ventricular fibrillation cardiac arrest model in which, after resuscitation and ventilation on either 100% O 2 (hyperoxic) or 21-30% O 2 (normoxic), animals were sacrificed at 2 h reperfusion and the brains removed for enzyme activity and immunoreactivity measurements. Animals resuscitated under hyperoxic conditions exhibited decreased PDHC activity and elevated 3-nitrotyrosine immunoreactivity in the hippocampus but not the cortex, compared to nonischemic controls. These measures were unchanged in normoxic animals. In vitro exposure of purified PDHC to peroxynitrite resulted in a dose-dependent loss of activity and increased nitrotyrosine immunoreactivity. These results support the hypothesis that oxidative stress contributes to loss of hippocampal PDHC activity during cerebral ischemia and reperfusion and suggest that PDHC is a target of peroxynitrite. KeywordsMitochondria; Hyperoxia; Nitrotyrosine; Normoxia; Oxidative stress; Global ischemia; Selective vulnerability; Free radicals Global cerebral ischemia and reperfusion cause severe neurochemical alterations, including oxidative modifications to lipids, proteins, and DNA. These and other covalent modifications can impair enzyme activities, including those necessary for energy metabolism. Alterations in these enzyme activities can limit postischemic aerobic metabolism and cellular ATP regeneration, thereby contributing to the pathophysiology of delayed neuronal cell death [1][2][3][4]. One enzyme known to be targeted and inactivated by reactive oxygen species is the pyruvate dehydrogenase complex (PDHC) [5]. Effects of ischemia/reperfusion on the PDHC can be particularly devastating because this enzyme forms the bridge between glycolysis and the Krebs cycle and can be the rate-limiting step in aerobic cerebral energy metabolism. NIH Public Access Author ManuscriptFree Radic Biol Med. Author manuscript; available in PMC 2008 October 21. Published in final edited form as:Free Radic Biol Med. 2006 June 1; 40(11): 1960-1970. doi:10.1016/j.freeradbiomed.2006.01.022. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe PDHC is located exclusively in the mitochondrial matrix and catalyzes the oxidative decarboxylation of pyruvate to form NADH and acetyl coenzyme A-the primary form of carbon that enters the Krebs cycle in the adult brain. Several laboratories have shown that PDHC enzyme activity is lost during cerebral ischemia/reperfusion [6][7][8]. PDHC im...

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Nitration and inactivation of manganese superoxide dismutase in chronic rejection of human renal allografts.

Cited by 738 publications

References 66 publications

Superoxide as a Messenger of Endothelial Function

Superoxide as a Messenger of Endothelial Function

Superoxide Dismutase Inactivation in Pathophysiology of Asthmatic Airway Remodeling and Reactivity

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

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